Our new amino acid, 2-iodo-L-histidine, is a potent antimalarial agent but undergoes rapid deiodination in vivo by cysteine or glutathione. The mechanisms of deiodination requires prior protonation of the imidazole ring; thus, 2,4-diiodohistidine is deiodinated at 1/10 the rate of 2- iodohistidine, because the second halogen reduces ring basicity to a significant degree. Unfortunately, the second iodine introduces extra steric bulk, which may be the reason the diiodo compound is biologically inactive. But the same reduction in basicity can be achieved with much smaller groups, and this fact provides a lead for new analogs. 4- (Trifluoromethyl)histidine has been iodinated at C-2, and the large trifluoromethyl group converted to the very small and very electronegative cyano group by exposure to aqueous ammonia. While histidine and its protected derivatives undergo bromination and iodination with extreme ease, chlorination has always proved almost impossible to achieve. We have found that "carbonylcyclohistidine", the bicyclic urea obtained by reaction of histidine ester with carbonyldiimidazole, undergoes chlorination very easily to produce both the mono and dichloro derivatives. Iodination of the monochloro derivative, followed by acid hydrolysis, provides the desired 4-chloro-2-iodo-L-histidine. As expected, 2-iodo-histidines containing strong electronegative groups at C- 4 do not undergo rapid deiodination by mercaptans. Examination of space-filling models reveals that 2-iodohistidine has a width corresponding exactly to the diameter of the erythrocyte membrane channel, as estimated from the diffusion rates of small molecules. The same dimension can be found in metabolically stable molecules, such as 1- isopropyl and 2-isopropylhistidine. A program was initiated to develop general synthetic methods for these previously inaccessible ring-alkylated histidines (and histamines). Several novel approaches have proved successful, and extensive series of 1-alkyl and 2-alkylhistidines are being prepared for screening.